{"doi":"10.1158/2159-8290.c.6548987.v1","title":"Data from SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies","abstract":"<div>Abstract<p>Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of <i>Arid1a, Arid2</i>, or <i>Smarcb1</i> in mouse BRAF<sup>V600E</sup>-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAF<sup>V600E</sup>-mutant mouse papillary thyroid cancers have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid-differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition. Loss of individual SWI/SNF subunits in BRAF tumors leads to a repressive chromatin state that cannot be reversed by MAPK pathway blockade, rendering them insensitive to its redifferentiation effects. Our results show that SWI/SNF complexes are central to the maintenance of differentiated function in thyroid cancers, and their loss confers radioiodine refractoriness and resistance to MAPK inhibitor–based redifferentiation therapies.</p>Significance:<p>Reprogramming cancer differentiation confers therapeutic benefit in various disease contexts. Oncogenic BRAF silences genes required for radioiodine responsiveness in thyroid cancer. Mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage specification genes in <i>BRAF</i>-mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade.</p><p><i>This article is highlighted in the In This Issue feature, p. 995</i></p></div>","journal":null,"year":2023,"id":405962,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9522,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":277156,"name":"Luis J. Leandro‐García","orcid":"0000-0002-7757-2408","position":1,"is_corresponding":false},{"id":262960,"name":"Jesper L.V. Mååg","orcid":"0000-0002-2578-8872","position":2,"is_corresponding":false},{"id":277157,"name":"Vatche Tchekmedyian","orcid":"0000-0002-6656-7427","position":3,"is_corresponding":false},{"id":277158,"name":"Gnana P. Krishnamoorthy","orcid":"0000-0002-6139-5435","position":4,"is_corresponding":false},{"id":279728,"name":"Prasanna P. Tamarapu","orcid":null,"position":5,"is_corresponding":false},{"id":277159,"name":"Vera Tiedje","orcid":"0000-0003-3612-0779","position":6,"is_corresponding":false},{"id":240162,"name":"Vincent Reuter","orcid":"0000-0002-7967-976X","position":7,"is_corresponding":false},{"id":277160,"name":"Jeffrey A. Knauf","orcid":"0000-0003-4456-8792","position":8,"is_corresponding":false},{"id":225995,"name":"Elisa de Stanchina","orcid":"0000-0002-3873-315X","position":9,"is_corresponding":false},{"id":250488,"name":"Bin Xu","orcid":"0000-0003-4638-9835","position":10,"is_corresponding":false},{"id":277161,"name":"Xiao-Hui Liao","orcid":"0000-0002-9860-2709","position":11,"is_corresponding":false},{"id":277162,"name":"Samuel Refetoff","orcid":"0000-0003-0164-8231","position":12,"is_corresponding":false},{"id":13486,"name":"Ronald Ghossein","orcid":"0000-0003-2802-8489","position":13,"is_corresponding":false},{"id":245664,"name":"Ping Chi","orcid":"0000-0002-0159-5531","position":14,"is_corresponding":false},{"id":235764,"name":"Alan L. Ho","orcid":"0000-0002-6885-3742","position":15,"is_corresponding":false},{"id":240165,"name":"Richard P. Koche","orcid":"0000-0002-6820-5083","position":16,"is_corresponding":false},{"id":108810,"name":"James A. Fagin","orcid":"0000-0002-2365-2517","position":17,"is_corresponding":false},{"id":277155,"name":"Mahesh Saqcena","orcid":"0000-0002-2210-3444","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T01:20:59.152593Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}